European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for appendiceal neuroendocrine tumours (aNET).

The aim of the present guidance paper is to update the previous ENETS guidelines on well differentiated appendiceal neuroendocrine tumours (NET), providing practical guidance for the diagnosis and management of appendiceal NET (aNET); poorly differentiated neoplasms are dealt with in a separate guidance paper. This paper is structured on a question-answer format in order to also address controversial issues and areas where uncertainty regarding the management and follow-up of aNET exists. All recommendations are offered on the basis of the best available evidence, along with the authors' experiences in managing these neoplasms. Each recommendation for treatment will provide a level of evidence and grade of recommendation as per the GRADE system (adapted in Infectious Disease Society of United States Public Health Service grading system).

European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for gastroduodenal neuroendocrine tumours (NETs) G1-G3.

The aim of the present guidance paper was to update the previous ENETS guidelines on well-differentiated gastric and duodenal neuroendocrine tumours (NETs), providing practical guidance for specialists in the diagnosis and management of gastroduodenal NETs. Type II gastric NETs, neuroendocrine carcinomas (NECs), and functioning duodenal NETs are not covered, since they will be discussed in other ENETS guidance papers.

The Role of Alternative Lymph Node Classification Systems in Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NEN): Superiority of a LODDS Scheme Over N Category in Pancreatic NEN (pNEN).

Lymph node (LN) involvement in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) has been reported to have prognostic and therapeutic implications. Numerous novel LN classifications exist; however, no comparison of their prognostic performance for GEP-NEN has been done yet. Using a nationwide cohort from the German Neuroendocrine Tumor (NET) Registry, the prognostic and discriminatory power of different LN ratio (LNR) and log odds of metastatic LN (LODDS) classifications were investigated using multivariate Cox regression and C-statistics in 671 patients with resected GEP-NEN. An increase in positive LN (pLN), LNR, and LODDS was associated with advanced tumor stages, distant metastases, and hormonal functionality. However, none of the alternative LN classifications studied showed discriminatory superiority in predicting prognosis over the currently used N category. Interestingly, in a subgroup analysis, one LODDS classification was identified that might be most appropriate for patients with pancreatic NEN (pNEN). On this basis, a nomogram was constructed to estimate the prognosis of pNEN patients after surgery. In conclusion, a more accurate classification of LN status may allow a more precise prediction of overall survival and provide the basis for individualized strategies for postoperative treatment and surveillance especially for patients with pNEN.

Prognostic factors after resection of locally advanced non-functional pancreatic neuroendocrine neoplasm: an analysis from the German Cancer Registry Group of the Society of German Tumor Centers.

OBJECTIVE: The available literature regarding outcome after pancreatic resection in locally advanced non-functional pNEN (LA-pNEN) is sparse. Therefore, this study evaluates the current survival outcomes and prognostic factors in after resection of LA-pNEN. MATERIALS AND METHODS: This population-based analysis was derived from 17 German cancer registries from 2000 to 2019. Patients with upfront resected non-functional non-metastatic LA-pNEN were included. RESULTS: Out of 2776 patients with pNEN, 277 met the inclusion criteria. 137 (45%) of the patients were female. The median age was 63 ± 18 years. Lymph node metastasis was present in 45%. G1, G2 and G3 pNEN were found in 39%, 47% and 14% of the patients, respectively. Resection of LA-pNEN resulted in favorable 3-, 5- and 10-year overall survival of 79%, 74%, and 47%. Positive resection margin was the only potentially modifiable independent prognostic factor for overall survival (HR 1.93, 95% CI 1.71-3.69, p value = 0.046), whereas tumor grade G3 (HR 5.26, 95% CI 2.09-13.25, p value < 0.001) and lymphangiosis (HR 2.35, 95% CI 1.20-4.59, p value = 0.012) were the only independent prognostic factors for disease-free survival. CONCLUSION: Resection of LA-pNEN is feasible and associated with favorable overall survival. G1 LA-pNEN with negative resection margins and absence of lymph node metastasis and lymphangiosis might be considered as cured, while those not fulfilling these criteria might be considered as a high-risk group for disease progression. Herein, negative resection margins represent the only potentially modifiable prognostic factor in LA-pNEN but seem to be influenced by tumor grade.

[Curative Treatment of Esophageal Carcinoma - Disease, Diagnostics, Therapy in 2022]. / Kurative Therapie des Ösophaguskarzinomes.

Curative Treatment of Esophageal Carcinoma - Disease, Diagnostics, Therapy in 2022 Abstract. Surgical resection remains the gold standard for non-metastatic carcinoma of the lower and middle third of the esophagus. Locally advanced tumors (T3) are pretreated neoadjuvantly (radiochemotherapy) or perioperatively (chemotherapy). A differentiated primary staging and an interdisciplinary case presentation are of essential importance today. The individual risk assessment, the pre-habilitation and the individualized treatment play a major role. Clinically, the further advancement of access minimization - through laparoscopic/thoracoscopic and robot-assisted procedures and the associated reduction of access trauma - as well as the treatment of this entity in high volume centers are clearly in the foreground. For cervical carcinomas definitive radiotherapy is often the better alternative, both for tumor biological reasons and for reasons of the increase in complications during surgery.

[Endoscopic Interventional Treatment of Precancerous Lesions and Early Carcinoma of the Esophagus - Criteria and Techniques of Local Ablation and Resection]. / Endoskopisch interventionelle Behandlung von Malignitätsvorstufen und des Frühkarzinomes des Ösophagus.

Endoscopic Interventional Treatment of Precancerous Lesions and Early Carcinoma of the Esophagus - Criteria and Techniques of Local Ablation and Resection Abstract. Early carcinomas of the esophagus can safely be resected endoscopically and interventionally under very strict conditions (ER). In contrast to ablative procedures (radiofrequency ablation, cryo-ablation, argon plasma coagulation, photodynamic therapy), which can only be recommended for Barrett's or low-grade dysplasia, ER - which is called EMR (endoscopic mucosal resection in adenocarcinoma) or more in-depth ESD (endoscopic submucosa dissection in squamous cell carcinoma) - a defined, histologically examinable preparation. This is required starting with high-grade dysplasia, since 50% of patients with biopsy-confirmed high-grade dysplasia after ER already have an invasive carcinoma in the specimen. This diagnostic gap is thus also closed with an interventional ER. ER is therefore an option for high-grade dysplasia in Barrett's, carcinoma in situ (Cis) and conditionally in T1a (adeno- and squamous cell carcinoma) and early T1b tumors (adenocarcinoma).

Anxiety, Depression and Quality of Life in Patients with Neuroendocrine Neoplasia After Surgery.

BACKGROUND: Neuroendocrine neoplasia (NEN) are rare and complex, with surgery as key therapy even in cases with metastasis. Little is known regarding the quality of life, prevalence of depression, anxiety and the impact of surgery. METHODS: This prospective, follow-up study included 90 consecutively recruited patients with NEN after surgery in a university hospital. The EORTC QLQ-C30, EORTC QLQ-GI-NET.21, and Hospital Anxiety and Depression Scale and a hospital specific questionnaire were completed during follow-up after 3 to 5 years (t1-t5). RESULTS: Mean age was 54 (SD 15) years, 13% had secondary malignancies and 11% had psychiatric diagnoses (depression n = 8, schizophrenia n = 2) pre-existent. Critical life events occurred in 51% within 5 years before diagnosis. Surgery was done in curative intention in 82% and R0-resection rate was 90%. The median survival was 25.3 years. The 10-year survival rate was 87%, 98%, 95% and 26% for all patients (n = 90), stage I/II (n = 45), stage III (n = 25) and stage IV (n = 20), respectively (p < .001). Anxiety score was pathological in 30% after 1 year (t1) and in 10% after 5 years, depression score in 25% (t1) and 30% (t5). Fatigue and muscle/body pain were elevated symptoms with > 50 and 40 points 3 years after surgery. CONCLUSION: Depression rate remains high whereas anxiety declines over time. Fatigue and muscle/body pain were identified as relevantly elevated after surgery. Systematic screening and supportive therapy should be implemented during follow-up after surgery.

[Neuroendocrine Neoplasia of the digestive tract]. / Neuroendokrine Neoplasien des Verdauungstraktes.

Neuroendocrine Neoplasia of the digestive tract Abstract. Neuroendocrine neoplasia are a rare and heterogenous tumor entity with long median survival even in metastatic situation. Surgery is the key therapeutic option although a wide range of other therapies are available in metastatic situation. Milestones in classification and grading were achieved by the European Neuroendocrine Tumor Society (ENETS) leading to practical guidelines and WHO- and TNM-classification comparable to the colorectal carcinoma. These new guidelines enable the handling of a rare and complex tumor entity.

Long-term outcome of surgical resection in patients with gastroenteropancreatic neuroendocrine neoplasia: results from a German nation-wide multi-centric registry.

BACKGROUND: Neuroendocrine neoplasia (NEN) are rare and heterogenous tumours. Few data exist on the impact of surgical therapy. MATERIALS AND METHODS: This is a retrospective analysis of prospectively collected data of gastroenteropancreatic NEN in the German NET-Registry (1999-2012). It focuses on patients without distant metastases (limited disease, LD, stage I-IIIB). RESULTS: Data of 2239 patients with NEN were recorded. Median age was 59 years, the gender ratio was 1:1.3 (f:m). A total of 986 patients (44%) had LD, and the 5-year survival rate (5 years) was 77% for all and 90% for patients with LD. A total of 1635 patients (73%) received a surgical therapy (1st to 6th line); the 5 and 10 ysr were 83/65% after and 59/35% without surgery for all patients (p < .001). The resection margins in the LD patients were 76%, 16%, and 3% for R0, R1 and R2, respectively. The 10 ysr was 84%, 59% and 42% for R0, R1 and R2 resections, respectively (p = .021 R0/R1, p < .001 R0/R2). The R0 resection rate was 75% for G1/G2 NET and 67% for G3 NEC. CONCLUSION: The rate of complete tumour resection (R0) in LD is independent of tumour grading, and R0 resection is the key determinant of long-term survival, as demonstrated by the 10 ysr. of 84%. All NEN patients with limited disease should be considered for operation, if possible, as the best 10-year survival is shown after an R0 resection.

Long-Term Outcomes of Surgical Management of Pancreatic Neuroendocrine Tumors with Synchronous Liver Metastases.

BACKGROUND: The value of surgical resection in the management of pancreatic neuroendocrine tumors (PNET) with liver metastases (LM) is still debated. The aim of this study was to evaluate the outcomes of surgery of PNET with LM. METHODS: Patients with PNET with synchronous LM between 2000 and 2011 from 4 high-volume institutions were included. The patients were divided into 3 groups: curative resection, palliative resection, and no resection. RESULTS: Overall, 166 patients were included. Eighteen patients (11%) underwent curative resection, 73 patients (43%) underwent palliative resection, and 75 patients (46%) underwent conservative treatment. The median overall survival (OS) from the time of diagnosis was 73 months. Patients who underwent curative resection had a significantly better median OS from the initial diagnosis compared with those who underwent palliative resection and those who were conservatively treated (97 vs. 89 vs. 36 months, p = 0.0001). The median OS from the time of diagnosis in those patients who underwent radical or palliative resection was 97 months, with a 5-year survival rate of 76%. On multivariate analysis, factors associated with OS from the time of diagnosis were the presence of bilobar metastases, tumor grading, and curative resection in a first model. On a second model, curative or palliative surgery was an independent predictor of OS. Among 91 patients who underwent surgery, the presence of pancreatic neuroendocrine carcinoma G3 was the only factor independently associated with a poorer survival after surgery (median OS: 35 vs. 97 months, p < 0.0001). CONCLUSIONS: Patients with LM from PNET benefit from surgical resection, although surgery should be reserved to well- or moderately differentiated forms.

Survival of diabetes patients with major amputation is comparable to malignant disease.

INTRODUCTION: Almost all studies on diabetic foot syndrome focused on prevention of amputation and did not investigate long-term prognosis and survival of patients as a primary outcome parameter. METHODS: We did a retrospective cohort study including 314 patients who had diabetic foot syndrome and underwent amputation between December 1995 and January 2001. RESULTS: A total of 48% of patients received minor amputation (group I), 15% only major amputation (group II) and 36% initially underwent a minor amputation that was followed by a major amputation (group III). Statistically significant differences were observed in comparison of the median survival of group I to group II (51 vs. 40 months; p = 0.016) and of group II to group III (40 vs. 55 months; p = 0.003). DISCUSSION: The prognosis of patients with major amputation due to diabetic foot syndrome is comparable to patients with malignant diseases. Vascular interventions did not improve the individual prognosis of patients.

CUP Syndrome in Neuroendocrine Neoplasia: Analysis of Risk Factors and Impact of Surgical Intervention.

BACKGROUND: Neuroendocrine neoplasia (NEN) with unknown primary site (NEN-CUP tumors) may have a poor prognosis. We evaluated the clinical presentation, therapy, outcome, and risk factors for adverse outcomes in patients who had these tumors. METHODS: In 243 patients who had NEN, a retrospective review was performed in 38 patients who had NEN-CUP tumors. The 38 patients who had NEN-CUP tumors were evaluated in three groups: group 1 (surgery; primary tumor detected; ten patients); group 2 (surgery; no primary tumor detected; ten patients); and group 3 (no surgery; 18 patients). Risk factors were evaluated with univariate and multivariate analyses. RESULTS: Most patients who had NEN-CUP tumors [32 patients (84%)] had World Health Organization (WHO) performance score of 0 or 1, and most tumors [24 patients (63%)] were well differentiated (WHO grade, G1 or G2; Ki-67 index, ≤20%). Univariate analysis showed that greater survival was significantly associated with lower patient age, lower WHO performance score, lower WHO grade, lower number of metastatic sites, treatment with surgery, and no treatment with chemotherapy. Multivariate analysis showed that low WHO performance score (hazard ratio 7.63, 95% confidence interval (CI) 2.63-22.19) and treatment with surgery (hazard ratio 0.10, CI 0.028-0.381) were significant independent predictors of improved survival. CONCLUSIONS: In patients with NEN-CUP tumors, surgical treatment is an independent predictor of better survival. Therefore, surgical treatment may be indicated in patients with good general health status and well-differentiated NEN-CUP tumors.

Genomic landscape of pancreatic neuroendocrine tumors.

AIM: To investigate the prognostic role of genomic stability and copy number alterations (CNAs) pancreatic neuroendocrine tumors (PanNETs). METHODS: A high-resolution array-based comparative genomic hybridization approach was utilized in order to investigate and quantify chromosomal aberrations in a panel of 37 primary PanNET and 11 metastatic samples. DNA samples were extracted from formalin-fixed and paraffin-embedded tumor specimen. Genomic findings were correlated with histopathological and immunohistochemical data. Moreover, the dataset was subjected to employing an unsupervised hierarchical clustering analysis approach utilizing Euclidean distance and average linkage and associations between genomically defined tumor groups and recurrent CNAs or clinicopathological features of the study group were assessed. RESULTS: Numerous chromosomal aberrations were recurrently detected in both, primary tumor samples and metastases. Copy number gains were most frequently observed at 06p22.2-p22.1 (27.1%), 17p13.1 (20.8%), 07p21.3-p21.2 (18.8%), 09q34.11 (18.8%). Genomic losses were significantly less frequent and the only recurrent aberration affected 08q24.3 (6.3%). Moreover, we detected a high degree of genomic heterogeneity between primary tumors and metastatic lesions. Unsupervised hierarchical clustering of loci affected by CNAs in more than 3 primary tumor samples revealed two genetically distinct tumor groups as well as two chromosomal clusters of genomic imbalances indicating a small subset of tumors with common molecular features (13.5%). Aberrations affecting 6p22.2-22.1, 8q24.3, 9q34.11 and 17p13.1 (P = 0.011; 0.003; 0.003; 0.001), were significantly associated with a poorer survival prognosis. CONCLUSION: This study suggests that several frequent CNAs in numerous candidate regions are involved in the pathogenesis and metastatic progression of PanNET.

Global microRNA profiling of pancreatic neuroendocrine neoplasias.

BACKGROUND: Pancreatic neuroendocrine neoplasms (pNEN) are rare tumors with a poor prognosis. Although increasing data have accumulated on the molecular pathology of pNEN, very scarce data exist on microRNAs in pNEN and no data are published on microRNAs as potential biomarkers of pNEN in serum. This study aimed to identify microRNA signatures of pNEN in tissue and serum. MATERIALS AND METHODS: We included tissue samples from 37 patients with pNEN, 9 patients with non-neoplastic pancreatic pathology, seven samples of micro-dissected pancreatic islets and serum samples of 27 patients with pNEN, as well as of 15 healthy volunteers. MicroRNA expression profiles were established using real-time quantitative Polymerase Chain reaction (PCR) for 754 microRNAs. RESULTS: MicroRNA signatures differed between pNEN, pancreatic islets and total pancreas, with virtually no overlap between the groups of de-regulated microRNAs. Expression of miR-642 correlated with Ki67 (MiB1) score and miR-210 correlated with metastatic disease. When comparing microRNA levels in serum from patients with pNEN and healthy volunteers, 13 microRNAs were more abundant in the serum of patients. MiR-193b was also up-regulated in pNEN tissue when compared to pancreatic islets and remained significantly increased in serum even when corrected for multiple testing. CONCLUSION: Evaluation of microRNAs appears to be promising in the assessment of pNEN. In particular, miR-193b, which is also increased in serum, may be a potential new biomarker of pNEN.

Spontaneous and non-spontaneous bleeding complications in patients with oral vitamin K antagonist therapy.

PURPOSE: The aim of the study was to evaluate potential differences between patients with spontaneous and non-spontaneous bleeding episodes during treatment with vitamin K antagonists which mainly resulted in compartment syndromes. METHODS: The population in this study comprised 116 patients who suffered at least one bleeding complication which required surgical treatment during therapy with an oral vitamin K antagonist. The patients were treated between September 2001 and July 2008. RESULTS: Significant differences were observed between the two patient groups with regard to the presence of renal failure, arterial hypertension, and diabetes mellitus, which occurred more frequently in patients with spontaneous bleeding. Also, significantly more patients with spontaneous bleedings developed compartment syndrome that needed emergency operation. Overall mortality was 9.6 %, was associated with multiorgan failure in all patients, and was not different between the two patient groups. CONCLUSIONS: The identification of high-risk patients before treatment with an oral vitamin K antagonist is of major importance. The existence of over-anticoagulation syndrome and compartment syndrome is associated with significant mortality and morbidity and should not be underestimated.